CHEK2 (Checkpoint kinase 2) is a tumor suppressor gene that encodes the protein CHK2, a serine-threonine kinase.
CHK2 is involved in DNA repair, cell cycle arrest or apoptosis in response to DNA damage.
Mutations to the CHEK2 gene have been linked to a wide range of cancers.
The CHEK2 gene is located on the long (q) arm of chromosome 22 at position 12.1.
The CHEK2 protein encoded by the CHEK2 gene is a serine threonine kinase, consisting of 543 amino acids.
It has the following domains:
N-terminal SQ/TQ cluster domain (SCD)
Central forkhead-associated (FHA) domain
C-terminal serine/threonine kinase domain (KD)
The SCD domain contains multiple SQ/TQ motifs that serve as sites for phosphorylation in response to DNA damage.
CHK2 appears as a monomer in its inactive state.
In the event of DNA damage SCD phosphorylation causes CHK2 dimerization.
The CHEK2 gene encodes for checkpoint kinase 2 (CHK2), a protein that acts a tumor suppressor.
CHK2 regulates cell division, and has the ability to prevent cells from dividing too rapidly or in an uncontrolled manner.
When DNA undergoes a double-strand break, CHK2 is activated.
DNA damage-activated phosphatidylinositol kinase family protein (PIKK) ATM phosphorylates site Thr68 and activates CHK2.
Activated CHK2 phosphorylates downstream targets including CDC25 phosphatases, responsible for dephosphorylating and activating the cyclin-dependent kinases (CDKs).
CHK2’s inhibition of the CDC25 phosphatases prevents entry of the cell into mitosis.
CHK2 protein interacts with several other proteins including p53 (p53).
Stabilization of p53 by CHK2 leads to cell cycle arrest in phase G1.
CHK2 is known to phosphorylate the cell-cycle transcription factor E2F1 and the promyelocytic leukemia protein (PML) involved in apoptosis.
The CHK2 protein plays a critical role in the DNA damage checkpoint, and mutations in the CHEK2 gene cause a wide range of cancers.
CHEK2 germline mutations rarely found among Li–Fraumeni syndrome (LFS) and 18 Li–Fraumeni-like (LFL) families, suggesting that CHEK2 is not a predisposition gene to Li–Fraumeni syndrome.
Inherited mutations in the CHEK2 gene have been linked to certain cases of breast cancer: Most notably, the deletion of a single DNA nucleotide at position 1100 in exon 10 (1100delC).
The loss of normal CHK2 protein function leads to unregulated cell division, accumulated damage to DNA and in many cases, tumor development.
The CHEK2*1100del mutation is most commonly seen in individuals of Eastern and Northern European descent: the CHEK2*1100delC mutation is seen in 1 out of 100 to 1 out of 200 of these individuals.
In North America the frequency drops to 1 out of 333 to 1 out of 500, but is almost absent in Spain and India.
A CHEK2 1100delC corresponds to a two-fold increased risk of breast cancer and a 10-fold increased risk of breast cancer in males.
A CHEK2 mutation I157T variant in the domain in exon 3 has also been linked to breast cancer but at a lower risk than the CHEK2*1100delC mutation: The estimated fraction of breast cancer attributed to this variant is reported to be around 1.2% in the US.
CHEK2 gene mutations, CHEK2*S428F, and CHEK2*P85L, have been found in the Ashkenazi Jewish population.
Mutations to CHEK2 have been found in hereditary and nonhereditary cases of cancer.
CHEK2 mutations are linked to cases of prostate, lung, colon, kidney, and thyroid cancers, and to certain brain tumors and osteosarcoma.
CHEK2 mutations do not appear to cause an elevated risk for ovarian cancer.
Squamous lung cancer has been described with a rare variant in CHEK2.
CHEK2 interacts with:
BRCA1
GINS2
MDC1
MSH2
MUS81
PLK1
PLK3